4UBA

Low-salt structure of protein kinase CK2 catalytic subunit with 4'-carboxy-6,8-bromo-flavonol (FLC26)

Summary for 4UBA

• Entry DOI: 10.2210/pdb4uba/pdb
• Related: 4UB7
• Descriptor: Casein kinase II subunit alpha, 4-(6,8-dibromo-3-hydroxy-4-oxo-4H-chromen-2-yl)benzoic acid (3 entities in total)
• Functional Keywords: protein kinase ck2, atp-competitive inhibitors, halogen bond, 4'-carboxy-6, 8-bromo-flavonol, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P68400
• Total number of polymer chains: 2
• Total formula weight: 81013.56

Authors

Niefind, K.,Bischoff, N.,Guerra, B.,Golub, A.,Issinger, O.-G. (deposition date: 2014-08-12, release date: 2015-07-01, Last modification date: 2024-05-08)

Primary citation

Guerra, B.,Bischoff, N.,Bdzhola, V.G.,Yarmoluk, S.M.,Issinger, O.G.,Golub, A.G.,Niefind, K.
A Note of Caution on the Role of Halogen Bonds for Protein Kinase/Inhibitor Recognition Suggested by High- And Low-Salt CK2 alpha Complex Structures.
Acs Chem.Biol., 10:1654-1660, 2015

PubMed Abstract: CK2 is a Ser/Thr kinase recruited by tumor cells to avoid cell death. 4'-Carboxy-6,8-dibromo-flavonol (FLC26) is a nanomolar CK2 inhibitor reducing the physiological phosphorylation of CK2 biomarkers and inducing cell death. Its binding mode to the ATP site was predicted to depend primarily on noncovalent interactions not comprising halogen bonds. We confirm this by two independent cocrystal structures which additionally show that FLC26 is selective for an open, protein kinase-untypical conformation of the hinge/helix αD region. The structures suggest how the bromo substituents, found previously in lead optimization studies, contribute to the inhibitory efficacy. In this context, one of the complex structures, obtained by crystallization with the kosmotropic salt NaCl, revealed an unconventional π-halogen bond between the 8-bromo substituent of FLC26 and an aromatic side chain which is absent under low-salt conditions. The kosmotropic salt sensitivity of π-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.

PubMed: 25961323
DOI: 10.1021/acschembio.5b00235

Experimental method

X-RAY DIFFRACTION (2.995 Å)